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Around 1950, Doll and Hill (Doll and Hill, 1950), Wynder and Graham (Wynder and Graham, 1950), and others reported the extremely high incidence of smoking in lung cancer patients. In fact, lung cancer was a rare disease before smoking (Doll and Hill, 1950). If one employs almost any method to assess causality, such as that proposed in the first Surgeon General's report on smoking (U.S. PHS, 1964) and later articulated in more detail by Sir Austin Bradford Hill (Hill, 1965), then clearly the use of tobacco products causes cancer. This conclusion comes from substantial epidemiology, laboratory animal, and in vitro studies. Tobacco smoke contains more than 100 carcinogens and mutagens, many of which are classified as carcinogens based upon human and animal studies (IARC, 1986), the latter include lung tumors in the same organs as cancers occur in humans. It is estimated that 20% of all cancers worldwide are attributable to smoking (Parkin et al., 1999).
If a regular smoker successfully quits, then the risk of cancer decreases, but the risk of cancer in former smokers does not decrease to the level of "never smokers." Thus, the concept of harm reduction by reducing exposure to tobacco carcinogens might be plausible if the exposure is significantly reduced, but the reduction in risk could not be more than that for a former smoker and would probably be less. Therefore, the most beneficial harm reduction strategy in smokers is to stop smoking.
The assessment of cancer risk from potential reduced-exposure agents (PREPs) must consider mechanisms of mutagenesis and carcinogenesis. This chapter will focus on only four types of cancer caused by cigarettes
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Around 1950, Doll and Hill (Doll and Hill, 1950), Wynder and Graham (Wynder and Graham, 1950), and others reported the extremely high incidence of smoking in lung cancer patients. In fact, lung cancer was a rare disease before smoking (Doll and Hill, 1950). If one employs almost any method to assess causality, such as that proposed in the first Surgeon General's report on smoking (U.S. PHS, 1964) and later articulated in more detail by Sir Austin Bradford Hill (Hill, 1965), then clearly the use of tobacco products causes cancer. This conclusion comes from substantial epidemiology, laboratory animal, and in vitro studies. Tobacco smoke contains more than 100 carcinogens and mutagens, many of which are classified as carcinogens based upon human and animal studies (IARC, 1986), the latter include lung tumors in the same organs as cancers occur in humans. It is estimated that 20% of all cancers worldwide are attributable to smoking (Parkin et al., 1999).
If a regular smoker successfully quits, then the risk of cancer decreases, but the risk of cancer in former smokers does not decrease to the level of "never smokers." Thus, the concept of harm reduction by reducing exposure to tobacco carcinogens might be plausible if the exposure is significantly reduced, but the reduction in risk could not be more than that for a former smoker and would probably be less. Therefore, the most beneficial harm reduction strategy in smokers is to stop smoking.
The assessment of cancer risk from potential reduced-exposure agents (PREPs) must consider mechanisms of mutagenesis and carcinogenesis. This chapter will focus on only four types of cancer caused by cigarettes
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and tobacco-containing products, although smoking causes other cancers as well (Doll, 1996); two of these are examples of the most common cancers related to tobacco (lung and oropharyngeal), and one is an example of a cancer that occurs remotely from the site of entry of the carcinogen into the body (bladder). The fourth cancer is one in which tobacco is believed to reduce risk (endometrial). In this chapter, a mutagen is defined as a compound that causes DNA damage of any sort. A carcinogen is defined as a compound that contributes to cancer, independent of the mechanism. A tobacco constituent is any compound from a tobacco-containing product, used in an intended or unintended fashion, which results in human exposure.
Cancers result from an accumulated amount of mutations (changes in nucleotide sequence) or gross chromosomal damage. There are several pathways to such DNA damage. Genetic damage occurs because a mutagen, or its activated metabolite, binds to or otherwise interacts with DNA. This mutagen can then cause a promutagenic lesion or in some other way perturb the genetic structure resulting in a gross chromosomal alteration (aneuploidy, break, translocation, amplification, deletion). The genetic damage follows a failure of several protective mechanisms. The first line of defense against chemical insult involves metabolizing enzymes that are intended to aid excretion of potentially damaging chemicals in the body (produced endogenously or coming from exogenous sources; Guengerich, 2000). For tobacco constituents, this "excretory" process gone wrong is a multistep pathway simplistically described as (1) entry of the mutagen into the body (i.e., oral, respiratory, and gastrointestinal mucosa) and its distribution throughout the body; followed by (2) recognition by an organ that this is a foreign substance in need of excretion (e.g., lung, liver, bladder); (3) use of enzymes for metabolic conversion of the chemical so that it can be bound to an excretory conjugate (Guengerich, 2000); (4) binding to DNA rather than an excretory conjugate; and (5) formation of a DNA adduct or a lesion that then results in DNA damage. A mutagen might be made more water soluble or able to bind an excretory conjugate (e.g., glutathione) through several chemical reactions catalyzed by cytochrome P-450 (CYP) and other enzymes, followed by conjugation catalyzed by enzymes (e.g., glutathione S-transferases, glucuronyl transferases, sulfuronyl transferases). Every one of these steps can influence cancer risk (Hecht, 1999a; Perera, 1997; Van Delft et al., 1998), where greater activity increases the risk of DNA damage, while greater conjugation and excretory capacity could reduce risk. Metabolic conversion and conjugate binding is a complex pathway that differs
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for different classes of mutagens, and there are redundant pathways (Anttila et al., 1992, 1993, 1995; Brennan, 1998; Grundy et al., 1998; Guengerich, 2000; Nakajima et al., 1995). Different parts of an organ such as the lung may have different capacities for activation and detoxification (Anttila et al., 1993; Bartsch et al., 1991; Geneste, 1991; Petruzzelli et al., 1989; Rojas et al., 1992; Shimada et al., 1996b). Enzymes that are responsible for metabolic activation and detoxification can be induced by exposures, which could further affect the level of subsequent DNA damage (Bartsch et al., 1995; Ciruzzi et al., 1998; Guengerich, 2000; McLemore et al., 1990; Nakajima et al., 1995). Thus, when manipulating the levels of carcinogens in tobacco products, it is important to consider how these changes might affect any of the above steps. Separately, it is well known that people have different heritable abilities for these steps, so manipulating the level of one or more tobacco product constituents might affect people differently.
If a mutagen binds to DNA, additional processes must fail before a mutagenic event occurs, and this takes place more often for some mutagens than for others. Thus, not all mutagens are human carcinogens. One form of DNA damage is a DNA adduct, which is a nucleotide with a chemically bound mutagen or some part of the mutagen. There may be some specificity for the sites of DNA adducts to occur within the genome, but adducts can form anywhere in the genome (La and Swenberg, 1996). Importantly, for the DNA adduct to contribute to the carcinogenic process, it must lead to a mutation and that mutation has to occur in a critical part of a critical gene.
Chemicals within the same class can have different capacities to form reactive intermediates and cause DNA-adduct formation in different parts of a gene. Therefore, simply altering the levels of a specific class in a harm reduction strategy might not affect the important chemical within that class, and the formation of a new adduct due to changes in chemical constituents might result in greater degrees of mutagenicity.
The chemical binding to DNA through the formation of adducts, for example, can lead to nucleotide sequence changes (insertions, deletions, or substitutions). It also can lead to gross chromosomal aberrations such as breaks, deletions, or translocations. These events occur when the mutagen causes errors during DNA replication or mitosis. However, there are protective mechanisms should any of these types of DNA damage occur and cancer develop due to the imbalance of DNA damage and DNA repair (Loeb and Loeb, 2000). Individual adducts may be repaired by excision repair pathways, while chromosomal aberrations are repaired by recombination repair pathways. In addition to DNA repair, other protective mechanisms can reduce the harmful effects of DNA damage, such as lengthening the G1 or G2 checkpoints to allow more time for DNA
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repair or triggering cell death (apoptosis). Unfortunately, some mutations might block the entry into these checkpoints or evade cell death processes. In addition to repair pathways that remove adducts, there are other control methods if these mechanisms or pathways fail. There are DNA repair enzymes that recognize and repair mismatch damage, and if this does not occur, cell death may be triggered. The combination of repair and cell turnover leads to a half-life of carcinogen-DNA adducts. To date, the effects of chemicals on these repair and control pathways, and interindividual differences in DNA repair, cell-cycle control, and cell death have only recently received some attention (Sumida et al., 1998).
The relationship between a mutagen and mutation is complex and may depend on the dose of the mutagen (La and Swenberg 1996; Van Delft et al., 1998). Low-dose exposures are often difficult to evaluate in vitro or in vivo because of mutational background rates, and extrapolation of mutation rates from high-dose to low-dose exposures depends on assumptions that may not be true (Liber et al., 1985). Mutation rates for exposures that switch from high dose to low dose and how the mutational spectra changes have not been studied.
In summary, for a tobacco constituent to cause a DNA lesion that confers a selective clonal advantage on a cell that ultimately becomes cancerous, the constituent must be absorbed and metabolically activated; it has to damage DNA, which evades repair; it has to occur in a critical part of a critical gene; and finally, the cell must evade cell death. Moreover, this has to occur in the target organ. Internal exposure can be affected by smoking behavior or storage depots in the body (e.g., adipose tissue). These pathways are important to consider for harm reduction strategies because altering the levels of different tobacco constituents or complex mixtures might affect these pathways differently, so that the net effect on carcinogenicity may not be predictable a priori, either for an individual or for the population.
Carcinogenesis is a multistage process involving many different genes (Devereux et al., 1999). DNA damage is necessary, but not sufficient, to cause tumors as evidenced in experimental models (Pledger et al., 1977). One conceptual approach to understanding carcinogenesis is to consider that cancer is driven by defects in either caretaker, gatekeeper, or landscaper genes (Kinzler and Vogelstein, 1997, 1998). Caretaker genes are those responsible for maintaining genomic integrity, such as DNA repair and metabolism. Mutations or inherited variants in these genes increase the risk of mutations in other genes. Gatekeeper genes are those involved in controlling cell cycle, and replication of the genome, triggering
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apoptosis, and assisting caretaker genes in maintaining genomic integrity. Mutations in gatekeeper genes increase the risk for a cell to replicate uncontrollably and increase the likelihood of permanently establishing mutations. Landscaper genes are those that affect the external environment around the cells and thus control adjacent cells. Current data do not exist to indicate that tobacco-related harm preferentially affects any classes of genes, but an effect of tobacco carcinogens on all classes of genes is plausible and suggested by the observed complex genetic alterations in lung and other cancers.
Another way to classify cancer genes is to consider them as oncogenes or tumor suppressor genes. This classification is based on studies showing that overexpression or mutation of the former increases proliferative potential, while loss of the latter stimulates proliferative potential. For oncogenes, only one allele has to be activated, whereas for tumor suppressor genes, both alleles are usually inactivated. Thus, the former is a dominant trait, while the latter is recessive.
Oncogenes occur when proto-oncogenes, responsible for normal cellular processes, are mutated. Multiple oncogenes are involved in the pathogenesis of solid tumors including lung cancer (Fong et al., 1999; Kohno and Yokota, 1999; Rom et al., 2000). Only a few oncogenes, such as K-ras and c-MYC have been identified as playing crucial roles in the pathogenesis of several tobacco-related tumors (Reynolds et al., 1991; Rodenhuis et al., 1987; Slebos et al., 1991, 1992). However, most oncogenes remain to be discovered. The ras gene family consists of three members (K, N, and H). They are membrane-bound proteins that bind to guanosine 5′-triphosphate (GTP) when activated, and to guanosine 5-diphosphate (GDP) when inactivated. Activation sends a signal to the nucleus, via a cascade of kinases, that eventually results in the activation of transcription factors. Activating ras mutations occur at codons 12, 13, and 61 and result in loss of intrinsic guanosine triphosphates (GTPase) activity, locking in the activated form (Bos, 1988); experimental studies support the role of tobacco carcinogens that affect ras in lung cancers (Ronai et al., 1993). It has been reported that ras mutations are present usually only in smoke-related lung cancers (Gealy et al., 1999; Slebos et al., 1991). Such mutations also can be observed in smokers without lung cancer, suggesting that they can be early markers of smoking-related damage (Lehman et al., 1996; Slebos et al., 1991; Scott et al., 1997; Yakubovskaya et al., 1995).
Tumor suppressor genes in tobacco-related cancers include p53 (also known as TP53), p16INK4A (p16), retinoblastoma (RB), and fragile histidine triad (FHIT) genes. A frequent method of inactivation of one allele of recessive oncogenes is by allelic deletion (i.e., loss of DNA material on one of the alleles). Often, this deletion is extensive and involves not only the gene of interest, but adjacent genes as well. The p53 gene is a tumor
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suppressor gene, and mutations of this gene may represent the most common genetic abnormality discovered to date in tumors, being present in about 50% of human carcinomas (Hollstein et al., 1996). It plays a central role in the balance between gene transcription, cell proliferation, and apoptosis. DNA damage results in the induction of genes upstream of p53 (Oren, 1999), which then stimulates p53 induction and stability through posttranslational modifications. This in turn affects p21, MDM2, GADD45, BAX, and other genes responsible for DNA repair, and delay of the cell cycle to allow additional time for DNA repair, or triggers cell death when DNA repair is not possible. The (p16) gene is located on chromosome 9p, and its protein plays a crucial role (along with the retinoblastoma gene product and the cyclins) in regulating the cell cycle. It is inactivated in many smoking-related cancers including non-small-cell lung, head and neck, and pancreatic cancer and squamous carcinomas of the esophagus (Geradts et al., 1999; Liu et al., 1995; Lydiatt et al., 1995), and occasionally bladder tumors (Orlow et al., 1999). Inactivation occurs by many mechanisms including hemizygous or homozygous deletions, point mutations, or aberrant methylation of the promoter region. The latter is an example of tobacco smoke constituents affecting genetic function without causing a mutation (i.e., an epigenetic change; Belinsky et al., 1998). The FHIT gene is a putative tumor suppressor gene located on chromosome 3p14 (Sozzi et al., 1998a, b). Inactivation of the gene product has been described in many tumors including lung, head and neck, and esophagus.
It might be possible to consider mutations in different genes as "molecular fingerprints" of causation by tobacco smoke for an individual. This could be helpful in considering the effects of different types of tobacco products and changes in tobacco constituents over time. It might also be possible to identify which tumors in an individual were caused by tobacco versus some other agent. However, no such "fingerprints" have been identified for tobacco smoking, although some types of lesions occur more frequently (Kondo et al., 1996). This may be due to the numerous carcinogens in tobacco, which cause many types of DNA damage. New microarray technologies will provide sequence data for many genes, RNA expression profiles or protein expression profiles that—with sufficient bioinformatic support—a characteristic profile could enable tobacco effects to be discerned.
Tobacco smoke exposes the entire respiratory and upper gastrointestinal mucosa to carcinogens, whereas smokeless tobacco exposes only the oral cavity and the gastrointestinal mucosa. Thus, these entire "fields" are at risk for the development of preneoplastic and neoplastic lesions (Slaughter et al., 1953; Strong et al., 1984). A field effect for cancer has been demonstrated on a molecular basis, where different molecular
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lesions were found in persons with multiple synchronous lesions (Sozzi et al., 1995).
The use of tobacco products, as they are intended to be used, results in exposure to more than 100 mutagens and carcinogens (Hoffman and Hoffman,1997; Zaridze et al., 1991) that have different potencies and effects. Mainstream smoke consists of particulate and vapor phases. Although carcinogens have been identified in both the vapor and the particulate phase, the latter shows more overall carcinogenic activity. The particulate phase contains more than 3,500 compounds, of which at least 55 have been identified as possible human carcinogens (Hoffman and Hoffman, 1997). The vapor phase contains more than 500 compounds (Hoffman and Hoffman, 1997). A list of some of these constituents is provided in Table 12–1, which is not all inclusive.
Tobacco mutagens and carcinogens have different potencies and target organ specificities. A recent critical review summarizing data for tobacco constituents proposed that tobacco-specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) are classes of compounds that most affect human cancer risk (Hecht, 1999b). Although this may be true, it is currently difficult to prove in human cancer, especially because these exposures are mixed with others. Other compounds also are likely to be important. The existing data are not sufficient to determine whether some compounds are clearly more carcinogenic in humans than others when delivered through the use of tobacco products, and whether there is a synergistic effect of coexposure. Therefore, the assessment of a harm reduction strategy for cancer must consider these constituents individually and as part of a complex mixture since the former can provide mechanistic information but only the latter can be used to fully understand the effect of PREPs on carcinogenesis.
Tobacco and tobacco products have changed over time, with resultant differences in predicted exposure using the Federal Trade Commission (FTC) method for the measurement of "tar" and "nicotine" (Hoffman and Hoffman, 1997). It is known that the FTC method for estimating tar exposure underestimates actual human exposure because it does not sufficiently mimic human smoking behavior (Hoffman and Hoffman, 1997). Specifically, using a protocol that mimics actual human smoking behavior shows that the FTC method substantially underestimates the exposure to TSNAs and benzo[a]pyrene [BaP] (Djordjevic et al., 2000). While smokers of low-nicotine cigarettes have somewhat lower delivered levels of BaP and TSNAs, the daily amount of tar delivered is similar (Djordjevic et
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TABLE 12–1 List of Selected Tobacco Mutagens and Carcinogensa
Constituent Class
IARC Evaluation
Sufficient in animals
Tobacco-specific nitrosamines (NNK, NNN), dimethylnitrosamine, diethylnitrosamine
Polycyclic aromatic hydrocarbons
Probable in humans
Benzo[a]pyrene, benzo[a]anthracene, benzo[b]fluoranthene, 5-methylchrysene
Sufficient in humans
4-Aminobiphenyl, 2-toluidine, 2-naphthylamine
Heterocyclic amines
Probable in humans
2-Amino-3-methylimidazo[4,5-[b]quinolone (IQ)
Organic solvents
Sufficient in humans
Benzene, methanol, toluene, styrene
Limited in humans
Acetaldehyde, formaldehyde
Volatile organic compounds
1,3-Butadiene, isoprene
Inorganic compounds
Sufficient in humans
Arsenic, nickel, chromium, polonium-210
aThis list is intended to provide a conceptual overview of the complexity of tobacco product exposures. It is not all inclusive, but is included to allow the reader to understand the number of considerations that must be made in assessing PREPs.
bInternational Agency for Research on Cancer: The classifications here refer to evaluations of the compound from any exposure, not just tobacco. Not all chemicals within the class are considered carcinogenic in humans. There is no consideration in this table of delivered dose or route of exposure.
NOTE: NNK=nitrosonornicotine ketone; NNN=N-nitrosonornicotine.
al., 2000). Therefore, in this report so-called tar yields do not imply actual tar exposure.
Although it is important to understand the differences in risks by chemical class, in order to assess PREPs, it must be realized that affecting the exposure to one compound or class might not account for similar proportional decreases of other compounds, and we do not know if removing one compound or even a whole class will reduce unless other classes of compounds are also decreased. Further, the study of mixtures
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(i.e., the real-life scenario of simultaneous exposure to many chemicals and classes) has received insufficient attention, and exposure to tobacco constituents as complex mixtures would provide the most compelling evidence for prediction of a successful PREP. Cigarette smoke condensate is mutagenic in bacterial and human cell lines (Matsukura et al., 1991) and can cause a malignant transformation in human bronchial epithelial cells (Klein-Szanto et al., 1992). Whole smoke, which is also mutagenic, can be used as well (Bombick et al., 1997). Both the vapor phase of environmental tobacco smoke (ETS) and unfiltered ETS exposure causes lung cancer in laboratory animals (Witschi et al., 1997a). There is some evidence to suggest that the mutational spectra of a complex mixture reflects mostly that of the dominant chemicals in the mixture (DeMarini, 1998), although experimental animal studies of DNA adducts from benzo[a]pyrene and coal tars indicate that total adduct levels are not related to BaP content alone (Goldstein et al., 1998), suggesting that studying single chemicals is not sufficient to represent the effects of complex mixtures. Further, various polycyclic aromatic hydrocarbons cause different hotspots in p53 (Smith et al., 2000), and different dose levels of complex mixtures might have additive or synergistic effects (Hecht et al., 1999; Poirier and Beland, 1992). Thus, more studies are needed to determine the best approaches to assess the mutagenicity and carcinogenicity of complex mixtures (Guengerich, 2000).
Several constituents of tobacco are considered likely agents of human carcinogenesis. Some of these are reviewed here to highlight the considerations needed in considering harm reduction strategies.
People are commonly exposed to PAHs through tobacco products, diet, occupation, and consumption of fossil fuels (i.e., burning coal or wood). These compounds are formed from the incomplete combustion of tobacco leaves, and many types of PAHs are present in tobacco smoke as a complex mixture. Parent PAHs can be detected in human lung tissue (Lodovici et al., 1998; Seto et al., 1993). It is estimated that smokers are exposed to 2–5µg of PAHs per day per pack of cigarettes, and our diet provides PAHs of 3µg per day (Hoffman and Hoffman, 1997; Lioy and Greenberg, 1990; Waldman et al., 1991). As a class, they are mutagenic and carcinogenic in organs of laboratory animals (including the lung) and humans (Hoffman and Hoffman, 1997; IARC, 1986; Van Delft et al., 1998). PAHs have different potencies, which are thought to be related to metabolic activation of a compound that leads to either a bay region diolepoxide (potent), or a fjord region diol-epoxide (nonpotent) compound. PAHs are metabolically activated in humans through CYP1A1, CYP1B1, and CYP3A4 (Kim et al., 1998; Shimada et al., 1996a). They are conjugated for excretion by glutathione S-transferases, sulfuronyl transferases, and glucuronyl transferases (Robertson et al., 1988), and the lack of such
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activity increases mutagenic potential (Romert et al., 1989). In laboratory animals treated with benzo[a]pyrene, the half-life of DNA adducts following a single dose is 15 days in the liver, 17 days in peripheral blood lymphocytes, and 22 days in lung (Ross et al., 1990). In humans, there is more than a hundredfold variation in the resultant capacity for DNA-adduct formation (Harris et al., 1974) due to variation in induction and activity for these activating and detoxifying enzymes. PAH-related DNA adducts have been demonstrated in human lung (Kato et al., 1995), while the presence of hemoglobin and albumin adducts also shows that these compounds circulate in human blood (Day et al., 1990; Kriek et al., 1998). In vitro studies indicate that PAHs can cause the same types of p53 mutations observed in human tumors (Denissenko et al., 1996; Smith et al., 2000). DNA damage from PAHs is repaired by both excision and recombination pathways, and while there is clearly interindividual variation in the DNA repair capacity of these pathways, such variation have received little attention for PAHs (Xu et al., 1998).
Tobacco products and smoke contain N-nitrosamines (Brunneman et al., 1996; Fischer et al., 1989b, 1990; Tricker et al., 1991), which are among the most potent rodent carcinogens (Lewis et al., 1997). Some of the N-nitrosamines in tobacco smoke are specific for tobacco, whereas others are the same types formed from dietary exposures. N-nitrosamines cause cancer in more than 40 animal species, and there is target organ specificity, including for TSNAs and lung tumors (Lewis et al., 1997; Rivenson et al., 1989), where there is a biphasic response in experimental animals indicating both a high affinity response at lower exposure levels and a saturation effect at higher levels (Belinsky et al., 1990; Pledger et al., 1977). Experimental animal studies also show that higher doses of exposure cause tumors in less time, suggesting that intensity and duration are equally important (La and Swenberg, 1996; Lewis et al., 1997). Mutations in K-ras have been found in lung tumors of experimentally exposed animals (Chen et al., 1993). TSNAs can transform human bronchial epithelial cells (Klein-Szanto et al., 1992). The same type of adducts that occur from TSNAs in experimental animals also have been detected in humans, including in lung tissue (Hecht et al., 1994). Different types of tobacco have different TSNA yields (Brunnemann et al., 1996). In humans, metabolites of TSNAs are found in urine (Carmella et al., 1993, 1995; Hecht et al., 1994), and adducts are detected in blood, so TSNAs circulate through the body, including in persons who are passively exposed (Atawodi et al., 1998; Hecht et al., 1993; Parsons et al., 1998). The elimination half-life of several TSNAs through the urine is estimated to be 40–45 days (Hecht et al., 1999). There is no mutational specificity for N-nitrosamines in several genes studied to date, although there is a propensity for G→A (guanine to adenine) transitions in experimental models (Chen et al., 1993; Ronai et al., 1993;
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Tiano et al., 1994). N-nitrosamines undergo metabolic activation by human cytochrome P-450s located in the lung, buccal mucosa, and other tissues (e.g., CYP2E1 and CYP2A6; Hecht, 1998; Patten et al., 1997; Smith et al., 1995, 1992). Ethanol induces CYP2E1 which may have implications for oropharyngeal and esophageal cancer (Garro et al., 1981; Ma et al. 1991). Cigarette smoking and exposure to other tobacco products increase endogenous nitrosation, so that there are additional exposures to nitroso compounds (Nair et al., 1996). The metabolic activation of TSNAs and other tobacco N-nitrosamines leads to the formation of DNA adducts in target tissues or is associated with specific cancers (Chang et al., 1990; La and Swenberg, 1996; Liu et al., 1993; Nesnow et al., 1994; Tiano et al., 1993; Yang et al., 1990; Zhang et al., 1991). TSNAs form three different classes of DNA adducts (Hecht, 1999a). The first involves methylation of different nucleotides, which also are formed by other N-nitrosamines, and some of these adducts are more promutagenic than others (O6-methylguanine more readily causes mutations than N7-methylguanine), and there are different repair enzymes for each. The O6-methylguanine is repaired by O6-alkyl-alkyltransferase. The activity of this enzyme varies among people and can be reduced in smokers, because once methylated it becomes inactive (Liu et al., 1997). Other classes of adducts formed by TSNAs, which are bulky (Atawodi et al., 1998; Hecht, 1999a), are probably repaired by nucleotide excision and recombination repair, similar to PAHs. The activity of these repair pathways also varies widely among individuals. Different tobacco products contain widely differing amounts of TSNAs (Fischer et al., 1989b). Snuff use can lead to higher levels of TSNAs than smoking (Hecht et al., 1994), and changing smoking patterns can result in higher delivery of TSNAs (Fischer et al. 1989a). For example, Swedish snuff products contain substantially fewer TSNAs than snuff sold in the United States. Lower-tar and nicotine cigarettes result in greater exposure to TSNAs than high-tar and nicotine cigarettes (Brunnemann et al., 1996; Hoffman and Hoffman, 1997). The third type of DNA adducts formed from TSNAs is related to oxidative damage (Hecht, 1999a).
Aromatic amines are another class of compounds present in tobacco smoke; these consist of aryl amines and heterocyclic amines. The latter are not reviewed here. There are substantial data to implicate aryl amines and their metabolism in human carcinogenesis (Vineis and Pirastu, 1997), especially bladder cancer in occupationally exposed cohorts (e.g., dye workers; Cartwright et al., 1982). In experimental animals, 4-aminobiphenyl (4-ABP) adduct levels increase in both liver and bladder tissues, but the rise in the bladder as a target organ is substantial and correlated with tumor incidence (Poirier and Beland, 1992). Saturation pathways might occur in female mice at lower doses than male mice, and saturation effects at higher levels of smoking have been reported in
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Virmani AK, Fong KM, Kodagoda D, et al. 1998. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 21(4):308–319.
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OCR for page 367
Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction
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Vanishing Seamanship
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Life is a wild ride!
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I think it all comes down to people. Some can learn from the mistakes of others or are capable of listening to sound advice without taking offense while others think it can't happen to them or don't want to be lectured to. My first boat was a 32' Endeavour. My only sailing experience was 20 years prior while daysailing with a friend on a Catalina 27 in San Diego, once in San Francisco, and once in Manilla Bay. Many on here may say that 32' was too much boat for a beginner. I would disagree. I disagree because from the start I respected the boat. She weighed 11,600 lbs and I had a good idea of how much damage that could do. I took her out in light winds. On my first trip I threw out an empty 2 liter bottle and made approaches to it both under power and under sail on a day there were very few other boats about. I spent over 4 hours approaching that bottle as if it was a concrete dock and I would sink if I hit it. I sunk my boat several times that day but all the sinkings were early on. I had much more confidence when I put her back in the slip.
I moved her shortly after that trip to a much larger lake. During the time of my move I realized I had made a very stupid mistake. I had learned 20 years ago that port tack/overtaking/windward boats must give way and powerboats give way to sail. When I got my copy of the navigation rules I realized their was so much more to know so I studied that book before I ever took her out again. I studied basic navigation. I got a current copy of the chart book for my area. My next trip was a weekend excursion on the lake. My only electronics was the depth meter and a handheld GPS unit. I followed my progress on the charts. Sure, I used the GPS but I knew exactly where I was on the chart at all times. With a 4'5" draft I mentally set a safe depth of 10'. Sand bars move so I kept a safe distance from the charted bars. When I actually anchored I had already selected a charted area with enough depth to allow me a 7:1 rode length with a clear 360 degree swing. I had my approach visualized and I had an escape plan if I needed it. It was a rather smallish cove. I had a great weekend of sailing even though the winds were only light to moderate. On the way back they were so light that I had to motor to get back before dark. The engine overheated. I cleaned the water strainer and restarted. Still overheating. Rather than tinker with it in the middle of a channel with barge traffic, I raised the sails and learned another lesson. Become better aquainted with a diesel engine. The long trip back at exactly 1 mph on my GPS and my 1st docking under sail taught me the folly of not knowing everything I could about my boat. Respect is not enough. I learned from my mistakes and have since made an effort to make sure those mistakes are not repeated.
If you've managed to stay with me this far then let me tell you how I could have done it. I could have jumped on that boat, backed her out of the slip without telling the people in the next slip it was my first boat and asking if they could lend a hand if needed, gunned the throttle and shoot out into the lake. I could have cruised around without knowing what was under my keel. Screw the practice, I can handle it. There are bumpers (yes, I know they are called fenders but I'm in character) on the boat so what the hell, let's have fun. On my weekend trip I would do the same thing. I don't need to read a book and I damn sure don't want to spend $15 on a chartbook. I have my GPS! Just keep it between the buoys! WOOHOOO!!!! What fun! Ok, drop the anchor. How much line to pay out? I'll tug on it. If I cant pull it up, then it should be fine. Damn engine overheated! Well, I'm in the middle of the channel. If anybody comes along they can see I'm not moving so they will avoid me while I spend the next hour or so reading the manual and figuring out what's wrong. Lucky thing I came back on deck. Why is that barge honking his horn? What the hell, he almost hit me! Who does he think he is? He don't own this lake. Guess I'll have to call the marina on the VHF for a tow. (On radio) "Hello, marina... Can you hear me?... This is Dean, can you come tow me in?"
My point in all this is that I think no matter what type of gadgets you have, or even if you have nothing, it boils down to people. It's whether or not you are willing to learn and have some respect for what you are doing and what you are doing it on. Society seems to have become so fast paced and trained us to rush to the goal and forget the milestones. Technology has enabled that mindset. It allows us to do without learning to do. You will NEVER hear me say "that can never happen to me" because that is when Karma will bite me in the butt. I owned my boat for a year before I had to sell her. In that year plus the day sails in San Diego I've experienced a lost rudder at the mouth of San Diego Bay, engine failure on the lake, and a broken prop shaft. I've had to dock single handed twice under sail. Once at night in calm conditions and once in daylight in very stressful conditions. I posted about that in the thread "Big Freakin Sails". So yes, it can happen to me, or anyone else no matter what your experience level. If you think it can't then I feel for you.
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group cohomology, nonabelian group cohomology, Lie group cohomology
cohomology with constant coefficients / with a local system of coefficients
differential cohomology
A line bundle is a vector bundle of rank (or dimension) , i.e. a vector bundle whose typical fiber is a -dimensional vector space (a line).
For complex vector bundles, complex line bundles are canonically associated bundles of circle group-principal bundles.
The class of line bundles has a nicer behaviour (in some ways) than the class of vector bundles in general. In particular, the dual? of a line bundle is a weak inverse of under the tensor product of line bundles. Thus the isomorphism classes of line bundles form a group.
Over any manifold there is canonically the density line bundle which is the associated bundle to the principal bundle underlying the tangent bundle by the determinant homomorphism.
See also at canonical line bundle.
The product of any space with the moduli stack of line bundles over it (its Picard stack) carries a tautological line bundle. This is called the Poincaré line bundle of .
moduli spaces of line n-bundles with connection on -dimensional


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Welcome to Aspen Country
Aspen Country specializes in uniquely themed home decor accents, fun garden decorations, eclectic home decorating accessories, stylish office decorations, artistic sculptures, unexpected kitchen decor accents, decorative accents, and unique motif decorations for the home and garden.
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Rustic Wagon Wheel Garden Decor: Two Tier Planter Box
Add a rustic touch of the country to your yard and enjoy your garden in a whole new way! Double-level planter box features a quaint wagon wheel theme and rustic brown finish, with plenty of room to proudly show off your favorite blooms. Fir wood. 21 1/8" x 13" x 22" high. Each planter 19" x 8" x 8" high. (Regularly $99.95) SALE!
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I used the Silhouette Cameo to cut my paper parts, but a good blade wielded by hand could easily do the same.
From the little triangles and squares, I used tacky glue to build likely shapes- they can be stuck right at the edges, even, for a pleasing geometric look.
I then formed my shapes into an imitation of the Mountain shelf, which can be seen in the gallery of the J1 Studio.
Prototyping in paper really helped me get a feel for how the structural components fit together, and how many of each component I needed. And now I have a miniature shelf!


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Ruby's Music Room
Ruby's Music Room is a vibrant and exciting live jazz venue in the heart of Melbourne's CBD. Situated on the corner of Little Lonsdale Street and Bennetts Lane, Ruby's bright yellow entrance is tucked neatly in a secret alleyway – to find it, one must pass her eclectic windows filled with interesting Cubano dolls, Maoist & New Orleanian memorabilia; miniature pianos, jewellery, menus, cigar wrappers, and kitsch collectibles from around the world.
Focusing on the thriving live music scene in Melbourne, Ruby's Music Room intends to thrill with live jazz, classical, and alternative performances in an intimate acoustic setting devoid of amps. Serving delicious food, fine wine and classic cocktails, Ruby's is the premier live music venue in Melbourne!
Additional Links
Music Network has facilities which include:
- Excellent Teaching Rooms
- Recital Room
- Waiting Room
- Accoustic Pianos
- Online Computer Facilities
- Rear Entrance
Ruby's Steinway D Concert Grand is kept in peak concert condition by Piano Boutique (contact Gregory Machnaki, ph: 04872840158).
cubano dolls exhibition
Cubano Dolls, comissioned by Ruby's Music Room.
The dolls are dressed by Maria de los Angeles Izquierdo Pequeños (known by everyone only as Maria), a Cubano artist living in Abel Santamaria, Havana.
A master seamstress, a teacher, and a speech therapist, she works her craft with wonderful hands and extraordinary imagination, joining two cultures distant in space and time: the Yoruba, a religion of Cuba, and the African culture inherited from the Congo and the Mandingo.
The dolls represent a history of slavery black women were submitted to, the sorrows and sadness which have run a long way since the 19th century. With Maria's natural grace and talent, each doll's apparel is a work of arts and a message of peace from the hot and hospitable Cuban land.


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Mr. ECO Kitchen Composter
Item # HN-EX060- Recycled plastic composter perfect for kitchen use
- Easily mounts to the wall and is airtight against odors
- Easy to clean and dishwasher safe
- Also for diapers and cat litter (don't add these to compost)
Recommended Accessory
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- Great design
- Keeps Smells Out
- Works Like Advertised
Best Uses
- Kitchen
Comments about Mr. ECO Kitchen Composter:
Impressive. Locks in odor just like advertised. it takes me about a week to fill the bin give or take, and then I take out and dump it in my big 75 gallon composter - extremely convenient. To give an idea of how much i cut up and compost im vagen. My roommates were very skeptical at first but now they are even composting. I would recommend it (for sure). Honestly, I didn't want to buy anything but my big outdoor composter, but this was a great idea and it has proven itself so far.
- Capacity
- Easy Assembly
- Odor Free
Best Uses
- Coffee Grounds
- Ecological Waste Disposal
- Fruit Rinds
- Kitchen Scraps
Comments about Mr. ECO Kitchen Composter:
The Mr. Eco Kitchen Composter has worked just as advertised. It comes with compostable bags that are a great addition, and don't get in the way of the turning lid. The lid takes a bit of effort to turn, but that's only because it has a tight seal which keeps odors in. So far, we are really happy with it - the size is great!
- Attractive
- Capacity
- Easy Assembly
- Difficult to use
Best Uses
- Coffee Grounds
- Ecological Waste Disposal
Comments about Mr. ECO Kitchen Composter:
I purchased this item because of the feature where the top rotates, dropping food into the container and then closing off any odors. Unfortunately, this only works when the biobag liners are NOT used, despite the fact that a few biobags are enclosed with the item.
Also, I asked the salesman on the telephone which refill bags to buy, however the ones he recommended are too small.
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This mid-size set of Aquarelle - Watercolor Made Easy sheets is great for your budding artist to shine! Each sheet measures 7.25" x 9.25".
Age | 8+ |
Manufacturer | Ravensburger |
Theme | Horses |
Product Type | Arts and Crafts |
Mfg. Part Number | 29320 |
UPC Number | 4005556293209 |
Release Year | 2013 |
Item Number | 70628 |
The in store location isn't a puzzle, but a set of coordinates to help you and our staff locate the item in our store. The item might be located in more than one place or could be in an area you don't have access to. If you have any problems locating the item, please ask for assistance and one of our friendly staff will help you.
Location(s): EC, 1, A


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Out for delivery
Posted 26 August 2014 - 08:52 AM
Posted 26 August 2014 - 09:22 AM
jfletcher67, on 26 August 2014 - 08:52 AM, said:
How about: "Guitar received intact"?
Looking forward to the pics...
AMPS & EFFECTS: Various effects, synths and Mesa Maverick 1 x 12.
Posted 26 August 2014 - 04:24 PM
With bated breath...
or somewhere
Lower and Warmer....
I like kayaking....it really floats my boat....
I dig most stuff....
Posted 26 August 2014 - 06:37 PM
jfletcher67, on 26 August 2014 - 06:07 PM, said:
Once you exceed the puny allotment you get here, you have to load your images to photobucket or some other free "storage" site, then use the 'img' (and '/img') tag with the url to your photo on that site to show them here. Nice 'clouds' on that guitar!
2003 Epiphone Masterbilt maple EF-500PNS
2008 Epiphone Masterbilt rosewood EF-500RAVS
2009 Epiphone Masterbilt mahogany EF-500MNS
2005 Epiphone Masterbilt cedar over rosewood AJ-500RC 12-fret
2014 Martin GPCPA4
2011 Epiphone Performer ME TBK
2013 Epiphone EL-00 Pro VS
1970-72 Epiphone FT-160 12-string
2012 Epiphone Dot CH
2013 Epiphone ES-339 Pro NA
2010 Epiphone Les Paul Standard trans amber
Posted 27 August 2014 - 09:39 AM
jfletcher67, on 26 August 2014 - 08:52 AM, said:
Are those full hollow or semi?
1997 - Fender California Edition HS Tele with a Rio Grande Pickups and a Warmoth Tele Neck
2000 - Gibson SG Special (Soon to me modded with a set of Gibson P-94's)
2003 - Fender American Deluxe HSS Strat with Rio Grande Pickups and a Warmoth Strat Neck
2009 - Gibson BB King "Lucille" Signature Model
2009 - Kala KA-T Tenor Ukulele
2011 - Martin D-28
2014 - Martin D-15M Burst
Egnater Tweaker Combo 40 Watt with a Weber 1x12
Fender Hot Rod Deluxe Extension Cab with a Weber 1x12
Acoustic B100 Bass Amp 100 Watt
Orange CrushPiX CRL20 20 Watt
Posted 27 August 2014 - 09:56 AM
jfletcher67, on 26 August 2014 - 08:52 AM, said:
"Out for delivery" is without a chance here. There are no greater three words than "I love you" in my opinion.
(The Fates lead the willing and drag those who are unwilling.)
Lucius Annaeus Seneca
Posted 27 August 2014 - 10:22 AM
FZ Fan, on 27 August 2014 - 09:39 AM, said:
the ES-137 are semi hollow bodies with a center block.
So they are like an ES-335, (Albeit just a bit thicker) or it's predecessor the ES-135.
I have one of the last year runs from the ES-135, fantastic guitar, I can't imagine the ES-137 to be anything short of excellent.
Congrats on the purchase, don't forget to write your review post haste!!
Posted 27 August 2014 - 03:41 PM
Kidblast - I was looking at a 135 as well, and you're right that those are fantastic guitars. I owned one briefly about 15 years ago and have regretted selling it for years. When it came down to it the price was right on the 137 so I went with it.
Posted 28 August 2014 - 02:36 AM
I could wax lyrical about these guitars for ever...
IMO the aesthetics are spot on...derived closely from the classic ES175
Being a semi...arguably there is more versatility and 'rockability'...
The design IMO is an inspired meld of ES175...ES335...Les Paul...
There is a mahogany insert in the maple centre block to veer the 'heavy ES335' thinking more toward 'Les Paul'...
Resulting in a classically 'archtop' styled guitar with the ability to handle more diverse musical styles...even to hi-gain blues and rock...
PS...Just looked at your pics and notice your's is the 'Classic' ES137 with the P/U's directly lifted from a Les Paul...
There is another 'Custom' ES137 with P/U's ('57's) directly lifted from a typical ES335, also with a Varitone circuit...
or somewhere
Lower and Warmer....
I like kayaking....it really floats my boat....
I dig most stuff....
Posted 28 August 2014 - 03:20 AM
*starts guitar window-shopping on the internet...*
Guitars... All fitted with GraphTech nuts & saddles; Schaller straplocks, and Levy's straps.
2002 Fender Squier Affinity Stratocaster ("Janus") in 2-tone Sunburst finish.
2013 Gibson USA Les Paul Traditional Pro II ("The Negroni") in Merlot finish. Gibson '57 Classic (neck) & Super '57 (bridge). TonePros locking bridge & tailpiece; Grover Roto-grips.
2014 Gibson USA 120th Anniversary Les Paul Studio ("The Screwdriver") in Honeyburst Vintage Gloss finish. Gibson 490R (neck) & 490T (bridge).
1978 Marshall Model 2195; Lead & Bass Head
Other Stuff...
Antoria Dreadnought Acoustic; Marshall Model MG15DFX.
Posted 28 August 2014 - 05:54 AM
My ES-135 is one of my Favs. I put a B7 Bigsby on her,, the final touch of coolness!
Posted 15 September 2014 - 10:43 PM
Posted 15 September 2014 - 11:00 PM
Considering size, the center block must have some weight to it, and so she also is nicely balanced I guess.
(The Fates lead the willing and drag those who are unwilling.)
Lucius Annaeus Seneca


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i don't mind the athetics so much but listening to the process that puts all those emty bottles there is a diferent matter. that is the overflow from the rubbishbin by the way and a perfectly normal night at home for them.
Albums: neighbours from hel
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*Can you think of any more? Pass along any suggestions to an Admin who will then add it to this list should it fit!
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Can anyone help to identify this font?
Please use the Edit link to move the thread up to the Type ID Board proper.
I actually think St. Regis' logo is custom. But, it looks alot like Engravers (depending on which version you have/find).


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Our Publications
GWPC and its partnering organizations have produced several reports and publications related to groundwater, source water, UIC, and oil and gas. Publications range from broad topic area pamphlets written for laymen and the general public, to more in-depth reports on topics such as shale gas and state groundwater regulations and processes.
Produced Water
The Ground Water Protection Council (GWPC) is pleased to provide an updated version of our 2009 report on U.S. Produced Water Volumes and Management Practices. This 2015 report, which contains data for 2012, discusses the amounts of water brought to the surface during oil and gas production and details many of the current minimization, treatment, re-use and disposal protocols used to manage produced water. It also contains state by state produced water summaries. The report was developed for the GWPC by John Veil of Veil Environmental, LLC. We think you will find this report both thorough and valuable.
Overview of Groundwater Protection Regulations in Oil and Gas States
This report is part of an update to the Ground Water Protection Council's 2009 Report, State Oil and Gas Regulations Designed to Protect Water Resources.1 The purpose is to document and outline the range of definitions and requirements for protecting groundwater, based on the regulations of oil and gas agencies and water quality protection agencies in 27 oil and gas producing states. The report is divided into two parts, the first documents the groundwater protection standards for oil and gas agencies and the second part addresses the standards for the water quality protection agencies within the same states. The scope is limited to an overview of regulations that address groundwater quality protection standards through policy statements, definitions, technical requirements such as well casing and cementing depths, groundwater classification and groundwater protection standards.
State Oil and Gas Regulations designed to protect water resources
In step with dramatic industry growth over the past five years, states have substantially improved groundwater
protection laws and regulations governing oil and natural gas production. State regulatory strategies
differ in response to unique local circumstances and characteristics; over time, they evolve to address
public concerns about the safety and environmental impact of oil and gas development, as well as rapidly
changing technologies, new field discoveries, revised leading operational practices, internal and external
reviews, and regulatory experience.
This Toolkit is a result of state and EPA collaboration. It could not have been developed without the time, effort and dedication of those who contributed to it and particularly the expertise of the state and EPA regional participants who are implementing the practices in this report.
White Paper II Summarizing a Special Session on Induced Seismicity
The topic of induced seismicity, or earthquakes caused by human activities, and in particular seismicity associated with hydraulic fracturing and disposal wells, has been the source of heightened interest and controversy over the past several years. To help disseminate factual information on the subject, the Ground Water Protection Council (GWPC) and its research arm, the Ground Water Research and Education Foundation (GWREF), decided to include sessions on induced seismicity in two of the organization's 2013 conferences.
An Assessment of State Needs for Regulating Geologic Sequestration of Carbon Dioxide
This report lays a foundation for states to accurately project additional personnel and associated costs and supporting capital outlay for a Class VI primacy program for "large-scale" geosequestration. The Underground Injection Control (UIC) program, expected to be the resident instrument for implementing the U.S. Environmental Protection Agency's sequestration regulatory program, has provided the framework for the safe and effective isolation of fluids injected underground for 30 years.
White Paper Summarizing 2012 Stray Gas Incidence & Response Forum
The purpose of the Forum was to explore the technical and scientific basis for stray gas investigations including the fundamentals of the physical and chemical properties of methane, and factors that influence the occurrence, migration, and fate of methane in the shallow subsurface environment. The conference agenda was structured to address the diverse topics and issues that should be considered during the course of an emergency stray gas incident response.
White Paper Summarizing 2013 Session on Induced Seismicity
This special technology transfer session for seismologists, regulators, and other stakeholders entitled "Assessing & Managing Risk of Induced Seismicity by Injection" was a part of the GWREF Spotlight Series.
State Oil & Gas Regulations Designed to Protect Water Resources
A review of state regulations designed to protect water from oil and gas activities.
State Oil & Gas Agency Groundwater Investigations
The role of state oil and gas agencies in protecting groundwater through investigation and regulatory reform.
Shale Gas Primer
A primer on the development of shale gas reservoirs through hydraulic fracturing and other means.
Injection Wells: An Introduction to Their Use, Operation and Regulation
An introductory brochure on the use, operation, and regulation of underground injection wells.
Ground Water Report
This link downloads the full report. Individual chapters can be downloaded from the "Programs" section of the website by clicking through to the specific topic. Groundwater Report links are at the bottom of each corresponding program page. Start by clicking the "PROGRAMS" link on the navigation toolbar above.


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In Nigeria, officials have fined e-waste importers $1 million. Earlier this month, officials intercepted a vessel just outside of Lagos that was carrying the banned material, reports AllAfrica. Nigerian law prohibits the carrying, depositing and dumping of harmful waste on any land or territorial waters in the country.
MBA Polymers has filed Patent Application 20130008831, which describes methods and devices for separating plastic materials from shredded electronics.
Electronics giant Samsung has introduced a line of upgradable TVs. Once it becomes commercially available in March, the company's "Evolution Kit" will plug into select Samsung TVs to upgrade them with voice controls, faster processors, and internet-enabled apps, obviating the need for consumers to discard their recent Samsung TV purchases in favor of newer models.
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Retirement Savings Account Providers Supervisory Levy Imposition Amendment Bill 2004
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Rights of the Terminally Ill (Euthanasia Laws Repeal) Bill 2008
Road Transport Charges (Australian Capital Territory) Repeal Bill 2008
Royal Commission (House of Representatives Elections) Bill 2003
Rural Adjustment Amendment Bill 1998
Rural Research and Development Legislation Amendment Bill 2013
Safe Climate (Energy Efficient Non-Residential Buildings Scheme) Bill 2009
Safe Climate (Energy Efficient Non-Residential Buildings Scheme) Bill 2010
Safe Work Australia Bill 2008
Same Sex Relationships (Ensuring Equality) Bill 2004
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